Blood-Brain Barrier in Neuroinflammation

描述（由申请人提供）：血脑屏障（BBB）通透性增加是中枢神经系统炎症的典型标志，发生在各种神经病理条件下。一般来说，血脑屏障通透性增加的范围从脑内皮细胞连接处的强化重塑（血管内皮细胞收缩，内皮细胞间连接蛋白的分布改变）导致细胞旁通路的大范围开放-血脑屏障分解到血脑屏障渗漏，这是一种对小分子大小化合物的选择性通透性，没有“可见”的TJ复合物重塑。血脑屏障渗漏见于许多疾病状态，如阿尔茨海默病和帕金森病、血管性痴呆和癫痫，但也见于缺血发作或炎症后血脑屏障恢复过程。目前对血脑屏障破坏中TJ改变的形态学改变和潜在机制的认识还不多，但对血脑屏障渗漏的改变类型和机制了解甚少。为了阐明缺血后炎症反应后持续血脑屏障渗漏的原因和机制，我们提出了一项研究计划，旨在验证以下假设：脑缺血/再灌注损伤后持续血脑屏障渗漏是由脑卒中后慢性炎症条件下发生的跨膜TJ蛋白结构改变引起的。本研究将确定；a)脑I/R损伤后TJ复合物和血脑屏障功能的特征，b)脑内皮细胞中TJ复合物紧密性和稳定性所必需的cladin蛋白-蛋白相互作用的类型，c)脑I/R损伤后血脑屏障延长渗漏调节的信号转导途径，d)卒中后改善脑内皮屏障的途径。总的来说，这些研究将提供与……有关的新信息

DESCRIPTION (provided by applicant): Increased blood-brain barrier (BBB) permeability represents a classic hallmark of central nervous system inflammation that occurs in a variety of neuropathological conditions. In generally the range of increase of BBB permeability goes from intensive remodeling of the brain interendothelial cell junction, (vascular endothelial cell contraction, altered distribution of endothelial intercellular junction proteins) which lead to wid "opening of paracellular route - BBB breakdown to BBB leakage, a selective permeability for small molecular size compounds without "visible" remodeling of TJ complex. BBB leaking is seen in many disease states like Alzheimer and Parkinson disease, vascular dementia, and epilepsy but also in the process of BBB recovery after ischemic episodes or inflammation. Insofar as the accumulating evidences define the morphological alteration and underlying mechanism of the TJ alteration in BBB breakdown, very little is know about type of alteration and mechanism of BBB leaking. In order to elucidate cause and mechanism of persistent BBB leakage develop after postischemic inflammatory response we propose a research plan directed at testing of the following hypothesis: The persistent leakage of BBB after brain ischemic/reperfusion injury is caused by structural alteration of transmembrane TJ proteins that develops in chronic post-stroke inflammatory conditions. The present study will determine; a) the characteristics of TJ complex and BBB functionality after brain I/R injury, b) the type of claudins protein-protein interactions essential for the tightness and stability of TJ complex in brain endothelial cells, c) the signal transduction pathways involved in regulation of prolonged leakage of BBB after brain I/R injury and d) the pathways that improve the brain endothelial barrier after stroke onset. Collectively, these studies will provide new information related to the mechanisms of BBB paracelluar permeability that is relevant to multiple disease states and will, hopefully, elucidate methods for controlling this event.